Cervical vertebral body growth and emergence of sexual dimorphism: a developmental study using computed tomography.

The size and shape of human cervical vertebral bodies serve as a reference for measurement or treatment planning in multiple disciplines. It is therefore necessary to understand thoroughly the developmental changes in the cervical vertebrae in relation to the changing biomechanical demands on the neck during the first two decades of life. To delineate sex-specific changes in human cervical vertebral bodies, 23 landmarks were placed in the midsagittal plane to define the boundaries of C2 to C7 in 123 (73 M; 50 F) computed tomography scans from individuals, ages 6 months to 19 years. Size was calculated as the geometric area, from which sex-specific growth trend, rate, and type for each vertebral body were determined, as well as length measures of local deformation-based morphometry vectors from the centroid to each landmark. Additionally, for each of the four pubertal-staged age cohorts, sex-specific vertebral body wireframes were superimposed using generalized Procrustes analysis to determine sex-specific changes in form (size and shape) and shape alone. Our findings reveal that C2 was unique in achieving more of its adult size by 5 years, particularly in females. In contrast, C3-C7 had a second period of accelerated growth during puberty. The vertebrae of males and females were significantly different in size, particularly after puberty, when males had larger cervical vertebral bodies. Male growth outpaced female growth around age 10 years and persisted until around age 19-20 years, whereas females completed growth earlier, around age 17-18 years. The greatest shape differences between males and females occurred during puberty. Both sexes had similar growth in the superoinferior height, but males also displayed more growth in anteroposterior depth. Such prominent sex differences in size, shape, and form are likely the result of differences in growth rate and growth duration. Female vertebrae are thus not simply smaller versions of the male vertebrae. Additional research is needed to further quantify growth and help improve age- and sex-specific guidance in clinical practice.

Essential anatomy for core clerkships: A clinical perspective.

Clerkships are defining experiences for medical students in which students integrate basic science knowledge with clinical information as they gain experience in diagnosing and treating patients in a variety of clinical settings. Among the basic sciences, there is broad agreement that anatomy is foundational for medical practice. Unfortunately, there are longstanding concerns that student knowledge of anatomy is below the expectations of clerkship directors and clinical faculty. Most allopathic medical schools require eight "core" clerkships: internal medicine (IM), pediatrics (PD), general surgery (GS), obstetrics and gynecology (OB), psychiatry (PS), family medicine (FM), neurology (NU), and emergency medicine (EM). A targeted needs assessment was conducted to determine the anatomy considered important for each core clerkship based on the perspective of clinicians teaching in those clerkships. A total of 525 clinical faculty were surveyed at 24 United States allopathic medical schools. Participants rated 97 anatomical structure groups across all body regions on a 1-4 Likert-type scale (1 = not important, 4 = essential). Non-parametric ANOVAs determined if differences existed between clerkships. Combining all responses, 91% of anatomical structure groups were classified as essential or more important. Clinicians in FM, EM, and GS rated anatomical structures in most body regions significantly higher than at least one other clerkship (p = 0.006). This study provides an evidence-base of anatomy content that should be considered important for each core clerkship and may assist in the development and/or revision of preclinical curricula to support the clinical training of medical students.

Ectopic expression of SOX9 in osteoblasts alters bone mechanical properties.

Osteoporosis is a common skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. We previously demonstrated that Col1a1-SOX9 transgenic (TG) mice, in which SOX9 specifically expresses in osteoblasts driven by a 2.3-kb Col1a1 promoter, display osteopenia during the early postnatal stage. In this study, to further analyze the osteopenia phenotype and especially the effect of the osteoblast-specific expression of SOX9 on bone mechanical properties, we performed bone geometry and mechanical property analysis of long bones from Col1a1-SOX9 TG mice and wild-type littermates (WT) at different time points. Interestingly, after body weight adjustment, TG mice had similar whole-bone strength as WT mice but significantly thinner cortical bone, lower elastic modulus, and higher moment of inertia. Thus, osteoblast-specific SOX9 expression results in altered bone structure and material properties. Furthermore, the expression levels of Pcna, Col1a1, osteocalcin, and the Opg/Rankl ratio in TG mice were significantly lower until 4 months of age compared with WT mice, suggesting that TG mice have dysregulated bone homeostasis. Finally, bone marrow stromal cells (MSCs) isolated from TG mice display enhanced adipocyte differentiation and decreased osteoblast differentiation in vitro, suggesting that osteoblast-specific expression of SOX9 can lead to altered mesenchymal stem cell differentiation potentials. In conclusion, our study implies that SOX9 activity has to be tightly regulated in the adult skeleton to ensure optimal bone quality.

Developmental morphology of the cervical vertebrae and the emergence of sexual dimorphism in size and shape: A computed tomography study.

Cervical vertebral bodies undergo substantial morphological development during the first two decades of life that are used clinically to visually determine skeletal maturation with the cervical vertebral maturation index (CVMI). CVMI defines six stages that capture the morphological transformations from 6 years to 18 years. However, CVMI has poor reproducibility given its qualitative nature and does not account for sexual dimorphism. This study aims to quantify the morphological development of the cervical vertebral bodies C2-C7 in size (height and depth) and shape and examine the emergence of sexual dimorphism. Using 115 (70 M;45F) computed tomography studies from typically developing individuals ages 6 months to 20 years, landmarks were placed at the margins of the C2-C7 cervical vertebral bodies in the midsagittal plane for size and shape analysis. Findings revealed a dichotomy in the growth trends of height versus depth. The C2-C7 growth in depth gained the majority of the adult size by age 5 years, while the C3-C7 growth in height displayed two periods of accelerated growth during early childhood and puberty. Significant sex differences were found in height and depth growth trends and the form-space ontogenetic trajectories during puberty, with minor but evident differences emerging at age 3 years. Female C2-C7 depth measures were smaller than males at all ages. However, sex differences in height became evident due to males continuing to grow after females reach maturity. Findings quantify the morphological developmental stages of CVMI and emphasize the need to account for sex differences when assessing skeletal maturation.

Conserved sequence in the aggrecan interglobular domain modulates cleavage by ADAMTS-4 and ADAMTS-5.

BACKGROUND: Cleavage of aggrecan by ADAMTS proteinases at specific sites within highly conserved regions may be important to normal physiological enzyme functions, as well as pathological degradation. METHODS: To examine ADAMTS selectivity, we assayed ADAMTS-4 and -5 cleavage of recombinant bovine aggrecan mutated at amino acids N-terminal or C-terminal to the interglobular domain cleavage site. RESULTS: Mutations of conserved amino acids from P18 to P12 to increase hydrophilicity resulted in ADAMTS-4 cleavage inhibition. Mutation of Thr, but not Asn within the conserved N-glycosylation motif Asn-Ile-Thr from P6 to P4 enhanced cleavage. Mutation of conserved Thr residues from P22 to P17 to increase hydrophobicity enhanced ADAMTS-4 cleavage. A P4' Ser377Gln mutant inhibited cleavage by ADAMTS-4 and -5, while a neutral Ser377Ala mutant and species mimicking mutants Ser377Thr, Ser377Asn, and Arg375Leu were cleaved normally by ADAMTS-4. The Ser377Thr mutant, however, was resistant to cleavage by ADAMTS-5. CONCLUSION: We have identified multiple conserved amino acids within regions N- and C-terminal to the site of scission that may influence enzyme-substrate recognition, and may interact with exosites on ADAMTS-4 and ADAMTS-5. GENERAL SIGNIFICANCE: Inhibition of the binding of ADAMTS-4 and ADAMTS-5 exosites to aggrecan should be explored as a therapeutic intervention for osteoarthritis.

Hyoid Bone Development: An Assessment Of Optimal CT Scanner Parameters and Three-Dimensional Volume Rendering Techniques.

The hyoid bone anchors and supports the vocal tract. Its complex shape is best studied in three dimensions, but it is difficult to capture on computed tomography (CT) images and three-dimensional volume renderings. The goal of this study was to determine the optimal CT scanning and rendering parameters to accurately measure the growth and developmental anatomy of the hyoid and to determine whether it is feasible and necessary to use these parameters in the measurement of hyoids from in vivo CT scans. Direct linear and volumetric measurements of skeletonized hyoid bone specimens were compared with corresponding CT images to determine the most accurate scanning parameters and three-dimensional rendering techniques. A pilot study was undertaken using in vivo scans from a retrospective CT database to determine feasibility of quantifying hyoid growth. Scanning parameters and rendering technique affected accuracy of measurements. Most linear CT measurements were within 10% of direct measurements; however, volume was overestimated when CT scans were acquired with a slice thickness greater than 1.25 mm. Slice-by-slice thresholding of hyoid images decreased volume overestimation. The pilot study revealed that the linear measurements tested correlate with age. A fine-tuned rendering approach applied to small slice thickness CT scans produces the most accurate measurements of hyoid bones. However, linear measurements can be accurately assessed from in vivo CT scans at a larger slice thickness. Such findings imply that investigation into the growth and development of the hyoid bone, and the vocal tract as a whole, can now be performed using these techniques.

Human evolution and osteoporosis-related spinal fractures.

The field of evolutionary medicine examines the possibility that some diseases are the result of trade-offs made in human evolution. Spinal fractures are the most common osteoporosis-related fracture in humans, but are not observed in apes, even in cases of severe osteopenia. In humans, the development of osteoporosis is influenced by peak bone mass and strength in early adulthood as well as age-related bone loss. Here, we examine the structural differences in the vertebral bodies (the portion of the vertebra most commonly involved in osteoporosis-related fractures) between humans and apes before age-related bone loss occurs. Vertebrae from young adult humans and chimpanzees, gorillas, orangutans, and gibbons (T8 vertebrae, n = 8-14 per species, male and female, humans: 20-40 years of age) were examined to determine bone strength (using finite element models), bone morphology (external shape), and trabecular microarchitecture (micro-computed tomography). The vertebrae of young adult humans are not as strong as those from apes after accounting for body mass (p<0.01). Human vertebrae are larger in size (volume, cross-sectional area, height) than in apes with a similar body mass. Young adult human vertebrae have significantly lower trabecular bone volume fraction (0.26±0.04 in humans and 0.37±0.07 in apes, mean ± SD, p<0.01) and thinner vertebral shells than apes (after accounting for body mass, p<0.01). Since human vertebrae are more porous and weaker than those in apes in young adulthood (after accounting for bone mass), even modest amounts of age-related bone loss may lead to vertebral fracture in humans, while in apes, larger amounts of bone loss would be required before a vertebral fracture becomes likely. We present arguments that differences in vertebral bone size and shape associated with reduced bone strength in humans is linked to evolutionary adaptations associated with bipedalism.

Trabecular microarchitecture of hominoid thoracic vertebrae.

Spontaneous vertebral fractures are a common occurrence in modern humans, yet these fractures are not documented in other hominoids. Differences in vertebral bone strength between humans and apes associated with trabecular bone microarchitecture may contribute to differences in fracture incidence. We used microcomputed tomography to examine trabecular bone microarchitecture in the T8 vertebra of extant young adult hominoids. Scaled volumes of interest from the anterior vertebral body were analyzed at a resolution of 46 microm, and bone volume fraction, trabecular thickness, trabecular number, trabecular separation, structure model index, and degree of anisotropy were compared among species. As body mass increased, so did trabecular thickness, but bone volume fraction, structure model index, and degree of anisotropy were independent of body mass. Bone volume fraction was not significantly different between the species. Degree of anisotropy was not significantly different among the species, suggesting similarity of loading patterns in the T8 vertebra due to similar anatomical and postural relationships within each species' spine. Degree of anisotropy was negatively correlated with bone volume fraction (r(2) = 0.85, P < 0.05) in humans, whereas the apes demonstrated no such relationship. This suggested that less dense human trabecular bone was more preferentially aligned to habitual loading. Furthermore, we theorize that trabeculae in ape thoracic vertebrae would not be expected to become preferentially aligned if bone volume fraction was decreased. The differing relationship between bone volume fraction and degree of anisotropy in humans and apes may cause less dense human bone to be more fragile than less dense ape bone.